Targeted adenovirus mediated inhibition of NF-κB-dependent inflammatory gene expression in endothelial cells in vitro and in vivo

J. M. Kułdo, S. A. Ásgeirsdóttir, P. J. Zwiers, A. R. Bellu, M. G. Rots, J. A C Schalk, K. I. Ogawara, C. Trautwein, B. Banas, H. J. Haisma, G. Molema, J. A A M Kamps

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

In chronic inflammatory diseases the endothelium expresses mediators responsible for harmful leukocyte infiltration. We investigated whether targeted delivery of a therapeutic transgene that inhibits nuclear factor κB signal transduction could silence the proinflammatory activation status of endothelial cells. For this, an adenovirus encoding dominant-negative IκB (dnIκB) as a therapeutic transgene was employed. Selectivity for the endothelial cells was achieved by introduction of antibodies specific for inflammatory endothelial adhesion molecules E-selectin or VCAM-1 chemically linked to the virus via polyethylene glycol. In vitro, the retargeted adenoviruses selectively infected cytokine-activated endothelial cells to express functional transgene. The comparison of transductional capacity of both retargeted viruses revealed that E-selectin based transgene delivery exerted superior pharmacological effects. Targeted delivery mediated dnIκB transgene expression in endothelial cells inhibited the induced expression of several inflammatory genes, including adhesion molecules, cytokines, and chemokines. In vivo, in mice suffering from glomerulonephritis, E-selectin-retargeted adenovirus selectively homed in the kidney to microvascular glomerular endothelium. Subsequent downregulation of endothelial adhesion molecule expression 2 days after induction of inflammation demonstrated the pharmacological potential of this gene therapy approach. The data justify further studies towards therapeutic virus design and optimization of treatment schedules to investigate their capacity to interfere with inflammatory disease progression.

Original languageEnglish
Pages (from-to)57-65
Number of pages9
JournalJournal of Controlled Release
Volume166
Issue number1
DOIs
Publication statusPublished - Feb 28 2013

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Transgenes
Adenoviridae
Endothelial Cells
E-Selectin
Gene Expression
Viruses
Endothelium
Pharmacology
Cytokines
Vascular Cell Adhesion Molecule-1
Therapeutics
Glomerulonephritis
Chemokines
Genetic Therapy
Disease Progression
Signal Transduction
Appointments and Schedules
Leukocytes
Chronic Disease
Down-Regulation

Keywords

  • Adenoviral gene therapy
  • E-selectin targeting
  • Endothelium
  • Inflammation
  • NF-κB inhibition

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Kułdo, J. M., Ásgeirsdóttir, S. A., Zwiers, P. J., Bellu, A. R., Rots, M. G., Schalk, J. A. C., ... Kamps, J. A. A. M. (2013). Targeted adenovirus mediated inhibition of NF-κB-dependent inflammatory gene expression in endothelial cells in vitro and in vivo. Journal of Controlled Release, 166(1), 57-65. https://doi.org/10.1016/j.jconrel.2012.12.016

Targeted adenovirus mediated inhibition of NF-κB-dependent inflammatory gene expression in endothelial cells in vitro and in vivo. / Kułdo, J. M.; Ásgeirsdóttir, S. A.; Zwiers, P. J.; Bellu, A. R.; Rots, M. G.; Schalk, J. A C; Ogawara, K. I.; Trautwein, C.; Banas, B.; Haisma, H. J.; Molema, G.; Kamps, J. A A M.

In: Journal of Controlled Release, Vol. 166, No. 1, 28.02.2013, p. 57-65.

Research output: Contribution to journalArticle

Kułdo, JM, Ásgeirsdóttir, SA, Zwiers, PJ, Bellu, AR, Rots, MG, Schalk, JAC, Ogawara, KI, Trautwein, C, Banas, B, Haisma, HJ, Molema, G & Kamps, JAAM 2013, 'Targeted adenovirus mediated inhibition of NF-κB-dependent inflammatory gene expression in endothelial cells in vitro and in vivo', Journal of Controlled Release, vol. 166, no. 1, pp. 57-65. https://doi.org/10.1016/j.jconrel.2012.12.016
Kułdo, J. M. ; Ásgeirsdóttir, S. A. ; Zwiers, P. J. ; Bellu, A. R. ; Rots, M. G. ; Schalk, J. A C ; Ogawara, K. I. ; Trautwein, C. ; Banas, B. ; Haisma, H. J. ; Molema, G. ; Kamps, J. A A M. / Targeted adenovirus mediated inhibition of NF-κB-dependent inflammatory gene expression in endothelial cells in vitro and in vivo. In: Journal of Controlled Release. 2013 ; Vol. 166, No. 1. pp. 57-65.
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